T cells are involved in many beneficial aspects of the immune system including the control of infections, tumor surveillance, generation of B cell responses, and regulation of homeostasis. In some instances, activated T cells are also detrimental to a host, mediating autoimmune disease, allergic reactions, immunopathology, and the rejection of transplanted tissues. The activation of naive T cells is a tightly controlled process, involving a complex network of signaling events that is still not completely understood. The early stages of T cell activation are critical to the programming of differentiation pathways for T cells, and this process is extremely sensitive to levels of inflammation. We have shown that naive phenotype T cells rapidly produce TNF within 5 hours of TCR engagement. This result was unexpected because naive T cells are thought to acquire effector functions only after undergoing a differentiation process and suggests that naive T cells produce this inflammatory cytokine during the innate phase of the immune response. Our recent data indicate that T cell-produced TNF has a suppressive effect on the generation of anti-viral responses, as TNF-deficient virus-specific T cells are present at significantly higher frequencies after infection as compared to wild type T cells. These findings reveal a novel self-regulatory function for antigen-specific T cells that is mediated by the production of TNF. The long-term goals for this proposed research plan are to further characterize the role of T cell-produced TNF in the generation of T cell responses and to determine if antagonizing TNF-activity at early times after infection will enhance immune responses. The specific hypothesis to be tested is that T cell- produced TNF has important regulatory functions for the development of functional cellular immunity. We propose to evaluate the importance of T cell-produced TNF by the following specific aims: SPECIFIC AIM#1: To determine the mechanisms by which T cell-produced TNF regulates the generation of virus-specific T cell responses. SPECIFIC AIM#2: To determine if a transient blockade of TNF-signaling will enhance the generation of virus-specific T cell responses after infection and vaccination. PUBLIC HEALTH RELEVANCE: The proposed research initiative will advance our basic understanding of how the immune system responds to infectious pathogens. The results of these studies may lead to the development of more effective vaccines that generate stronger anti-viral immunity.